Testosterone compositions



Oct. 7, l1958 R. MEIER ET AL TEsTosTERoNE con/(POSITIONS United `States Patent O 2,855,341 l y y TEsTosrERoNE coMPoslTIoNs Rolf Meier and Albert Wettstein, Basel, and Emil Lang, Riehen, Switzerland, assignors to Ciba Pharmaceutical Products Inc., Summit, N. J.

Application June 29, 1955, Serial l`vo.l,i18,7 38 Claims priority, application,Switzerland'luly 2, 1954 6 claims. (ci. 1mg-74) This invention relates to compositions having androgenic properties.' More particularly, this invention is concerned with compositions having androgenic properties comprising mixtures of testosterone undecylenate, -testosterone valerate and testosteronepropionate.

Various esters of testosterone moreparticularly-the propionate, have been widely used in recent years in the treatment of androgenic disorders.` They have been found to be primarily useful in testicular hormone`.'deciency of the male, and forthis reason are offvalue in the treatment of prepuberal and postpuberal e'unuchoidismA and hypogonadism; Other notable examples of valuable applications of thesetestosterone esters are in the treatment of the female in the control of menorrhagia and in post-partum inhibition of lactation and breast engorgement. t I

Among the least desirable aspects of ladministering these Vhormones from a clinical point of viewis the necessity for frequent administration in order to obtain a sustained drug eiect. In addition, in order to obtain a rapid onset, it is frequently necessary to administer extremely high doses. When the drugsare administered parenterally, as is frequentlythe case, the discomfort and pain associated with-such administration become extremely mportant-factorsfrom the viewpoint of both the physician and the patient. i f

We have now discovered thatwhen the undecylenyl, valeryl and propionyl esters of testosteroneV are combined in a mixture, the resultant composition is capable of effecting a rapid and protracted androgenic effect, not previously obtainable upon the administration of any .of these esters singularly.

Although the undecylenyl, valeryl and propionyl esters of testosterone may be combined in various proportions to obtain rapid and protracted' androgenic effects,v we

have found that mixtures rof the above-mentioned esters of testosterone in an approximate ratio of l :8:2 parts respectively are preferable. The content of the testosterone ester mixture in a preparation may vary between 0.01 to 50% by weight. A single dosage unit may contain a quantity varying from 0.5 to 500 mg. of the testosterone ester mixture.

The special therapeutic properties of the new hormone preparations can be proved, for example, by experiments on capons. For this purpose, by way of example indivdual doses of 2.5 mg. were administered intramuscularly as follows:

(l) l dose of the testosterone ester mixture according to the present invention, consisting of 1.5 mg. of testosterone undecylenate 0.8 mg. of testosterone valerate 0.2 mg. of testosterone propionate Total 2.5 mg. mixture (2) l dose of 2.5 mg. of testosterone undecylenate alone,

(3) l dose of 2.5 mg. of testosterone valerate alone,

(4) l dose of 2.5 mg. of testosterone propionate alone.

, i ,Y Patented Oct. 7, 1958 ICC The silhouette of the comb `was measured planimetrically and the growth expressed graphically las a percentage as shown in the accompanying drawing. 'Ihe individual curves represent average values of experiments with 4 to 7 capons. It is seen from them that a single dose of the mixture of they three testosterone esters according to this invention has a considerably stronger effect than that of any of the esters alone in the same dosage. A further particularA advantage of the new preparations consists in that, when compared with the individual esters, they have Ia more rapid onset and attainment of the maximum growth and a more protracted maximum growth.

The new testosterone ester preparations are prepared by conventional methods, for example withthe. use of pharmaceutical, organic or` inorganic carrier materials such as are suitable for parenteral, oral or topical application. Such substances are concerned as do not react with the testosterone esters, as for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, lactose, starch, magnesium stearate, talc, vaseline, cholesterol or other medicament carriers. Of especial importance are preparations for parenteral administration, preferably solutions, primarily oil solutions, and also suspensions, emulsions or implantates; in a corresponding manner tablets or drageesare produced for oral administration and salves or creams for topical application. If desired, the preparationsv can be sterilized or subjected to the addition of auxiliary materials such as preserving, stabilizing, wetting or emulsifying agents, salts for variation of the osmotic pressure or buffer substances or also other therapeutically valuable materials, for example, local anaesthetics or substances having an effect upon the blood vessels.

The following examples illustrate the invention:

EXAMPLE l )Oil ampoules` Benzyl alcol1o1 A 40 Sesame oil to 1 cc; t

The production of these` oil ampoules can be carried out as follows: v n

(I) The testosterone esters (undecylenate, valerate, propionate) are` mixed ,and ,finely ground. Then the benzyl alcohol is introduced Vand the whole heated on the water bath until solution results.

(II) The solution I is then diluted with sesame oil, so that l cc. of the resulting solution contains exactly 250 mg. of the testosterone esters.

(III) The solution is filtered in the customary manner and lilled into ampoules; the closes ampoules are heatsterilized by autoclaving with steam under pressure in accordance with the usual directions.

EXAMPLE 2 The testosterone Yesters are ground with sterile poly-- oxyethylene sorbitane `monolaurate and a small partof the suspension-agentadded in portions. The desired volume is made up with the remainder of the suspension agent. The suspension agent is prepared by dissolving the sodium carboxymethylcellulose in a quantity of distilled water Vand'dissolving vtherein theprimary and secondary sodium phosphate, the thimerosal and the sodium chloride. Before use, the suspension agent is heat-sterilized. The preparation and lling of the crystal ampoules is carried out-under aseptic conditions.

(I) The hormones are ground to a homogeneous mixture with a part of the lactose; mixing is then carried out with'the remainder of the lactose and the powdered sugar.

(II) The p-s'tearoylamino-phenyl-trimethylammonium methyl sulfate'is dissolved in three times its weight of alcohol and the hormone-powder mixture I moistened with the solution, granulated with a little water and dried.

(III) The lubricant is added and the whole tableted in units of appropriate dosage (supra).

The testosterone esters to be used according to this invention can be produced by known methods. Thus for example, the testosterone undecylenate is obtained in the following manner:

Into a solution, prepared in a dry nitrogen atmosphere, of 28.84 gm. of testosterone in 100 cc. of anhydrous benzene and 30.2 cc. of anhydrous pyridine, 27.0 cc. of undecylenyl chloride are introduced drop-Wise within 45 minutes with stirring and external cooling with water at 18-20 C. When the addition is complete, the mixture is stirred for a further hours at room temperature, then poured into 200 cc. of 2 N-sulfuric acid and the Whole extracted with ether. The ether extract is washed consecutively with 0.5N-sulfuric acid, water, 0.1 N-caustic soda solution and with water to a neutral reaction, dried with sodiu'msulfate and evaporated. The solvent-free residue is recrystallizedfrom anhydrous ethanol with cooling in a mixture of ice and common salt. By liltration with suction, washing with ethanol and drying at 25-28 C. under vacuum, pure testosterone undecylenate of the is obtained in colorless crystals of M. P. 52-53.5 C.

What is claimed is:

1. A composition having androgenic properties comprising testosterone undecylenate, testosterone valerate and testosterone propionate in an approximate ratio of 15 :8:2 parts by weight respectively.

2. A composition having androgenic properties comprising testosterone undecylenate, testosterone valerate and testosterone popionate in an approximate ratio of 15 :8:2 parts by weight respectively in a pharmaceutical carrier;

3. A composition having androgenic properties comprising from 0.01 percent by weight to 50 percent by weight of a mixture of testosterone undecylenate, testosterone valerate and testosterone propionate in an approximate ratio of 15:8:2 parts by weight respectively in a pharmaceutical carrier.

4. A composition having androgenic properties in dosage unit formcomprisingfrom 0.5 to 500 mg. of a mixture of testosterone undecylenate, testosterone valerate and testosterone propionate in a ratio of l5 :8:2 parts by weight and a sterile parenteral aqueous diluent.

5. A composition having androgenic properties in dosage unit form comprising from 0.5 to 500 mg. of a mixture of testosterone undecylenate, testosterone valerate and testosterone propionate in a ratio of 15:8:2 parts by weight and a sterile parenteral oily diluent.

6. A composition having androgenic properties in dosage unit form comprising from 0.5 to 500 mg. of a mixture of testosterone undecylenate, testosterone valerate and testosterone propionate in a ratio of l5 8 :2 parts by weight and a solid pharmaceutical carrier, said composition being in tablet dosage unit form.

OTHER REFERENCES Miescher: Biochem. I.,`vo1. 30, 1936, pp. 1977-1990. Parkes: I. of Endocrinology, vol. 4, 1944-45, p. 102. 

1. A COMPOSITION HAVING ANDROGENIC PROPERTIED COMPRISING TESTOSTERONE UNDERCYLENATE, TESTTOSTERONE VALERATE AND TESTOSTERONE PROPIONATE IN AN APPOROXIMATE RATIO OF 15:8:2 PARTS BY WEIGHT RESPECTIVELY. 